Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4 and CDK6, while other CDKs such as CDK7, CDK8 and CDK9 are critical to transcription. CDK binding to cyclins forms heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiates events required for cell-cycle transcription and progression. Since uncontrolled cell proliferation is a hallmark of cancer, and most cancer cells exhibit deregulation of CDKs, inhibition of CDKs has emerged as a potential treatment for various cancers. Inhibitors with varying degrees of selectivity for CDKs have been reported; however, selective CDK4/6 inhibitors are currently viewed as a promising class of potential anticancer or anti-inflammatory agents due to both the critical role of CDK4/6 in regulating cell proliferation and the toxic effects associated with inhibition of other members of the CDK family.
Recently, several types of aminopyrimidine derivatives have been reported to be selective CDK4/6 inhibitors. See, e.g., WO 2003/062236, WO 2007/140222, and US 2010/0160340. Each of these types of molecules contains a 2-aminopyrimidine moiety bound through the 2-amino group to an aryl or heteroaryl ring system. There remains a need to develop new CDK 4/6 inhibitors as novel anticancer and/or anti-inflammatory agents.